382 ABSTRACTS

NEPHROLOGY Recent studies have shown that the fetal kidney is limited in its ability to acidify the urine and to secrete hydrogen ions when The natural history of : Lightwood's syn- compared to the adult kidney. To further study H+ secretion and drome revisited. MARTIN A. NASH, ANTONIO D. TORRADO, EDDIE the ability of the fetal kidney to establish a pH gradient between S. MOORE, JUAN RODRIGUEZ-SORIANO, IRA GREIFER, ADRIAN SPIT- blood and urine, Na2SO4 was infused into the intact fetus. Albert Einstein Coll. of ZER, and CHESTER M. EDELMANN, JR. Studies were done on 7 near-term pregnant sheep and their Med., N. Y., N. Y. fetal lambs. The ewes were injected with DOCA and the fetuses Twelve children with primary renal tubular acidosis (RTA) were given cortisone acetate. This served to enhance renal tubular studied with HCO3" titration and NH4C1 loading have been reabsorption of Na+. Caesarean sections were performed and 75cc observed 1V&-8 yrs. These include 1 $ with proximal RTA of 8% Na2SO4 was infused into each fetus. Blood and urine sam- (PRTA) dx'd at 7-18 mos, and 3 $ and 2 9 with distal RTA ples were collected from the ewe and fetus. There were no sig- dx'd at 3-13 yrs. Bone disease and/or nephrocalcinosis were pres- nificant changes in fetal or maternal blood pressure, pulse, tem- ent in DRTA but not PRTA. GFR (CIN) at onset was normal or perature or pCO . slightly decreased in PRTA, but 40-60% of normal in DRTA. 2 The mean initial urine and blood pH in the fetus was 7.075 GFR is now normal in all patients. With rx pts had accelerated and 7.352 respectively. The mean minimum urine pH in the fetus growth, reaching at least the 3rd percentile in 2-3 yrs, with after Na SO was 5.2 with a range of 4.7-5.7. The mean minimum some achieving the 50th percentile. Five with PRTA have nor- 2 4 blood pH in the fetus after Na SO was 7.362. The mean urine pH mal blood pH and HCO off rx, 5-8 yrs after dx. Two remain 2 4 3 in the ewe before and after Na SO was 5.824 and 5.920 re- on rx <2 yrs after dx. The acidification defect in pts with 2 4 spectively. This is consistent with little or no transfer of SO = DRTA persists. Thus PRTA appears to be a self-limited dis- 4 across the placenta. The mean maximum TA and NH, excretion ease of bicarbonate reabsorption in male infants, characterized in the fetus was 4.35 and 8.21 /iEq/min/kg respectively. There by growth retardation and acidemia, without bone disease and was no correlation between fetal weight and response time be- nephrocalcinosis. DRTA appears to be a permanent defect in fore production of an acid urine. urinary acidification, with acidemia, growth retardation, bone dis- These studies indicate that in the intact fetal lamb, a stimulus ease, and nephrocalcinosis. Response to rx in both groups is good, + with marked improvement in growth, and normalization of (DOCA) to the fetal kidney to reabsorb Na without equivalent GFR in DRTA despite severe degrees of initial nephrocalcinosis. amount of anion results in intense acidification of the urine. On the basis of these observations, it seems likely that Light- The fetal kidney is thus able to establish a pH gradient with no woods's syndrome was proximal RTA—not distal RTA as has evidence of intrinsic limitation of hydrogen ion secretion. been considered heretofore. Pressure gradients for filtration in the developing kidney. ADRIAN SPITZER (Intr. by Chester M. Edelmann, Jr.). Albert Einstein Maturation of intrarenal blood flow distribution in newborn Coll. of Med., N. Y., N. Y. puppies. LEONARD I. KLEINMAN and JOHN H. REUTER (Intr. by It is well documented, both in humans and animals, that low I. Light). Univ. of Cincinnati Coll. of Med., Cincinnati, Ohio. rates of glomerular filtration prevail during early postnatal life. Intrarenal glomerular blood flow distribution was studied in 34 Although several explanations for this phenomenon have been newborn puppies ranging in age from 1 to 40 days using radio- offered, no direct measurements of the forces responsible for labeled carbonated microspheres 15-25 fi. The technique was vali- glomerular filtration in the developing animal are available. dated by histological sectioning, dual labeling of microspheres This information was sought in the present study by micro- and multiple sectioning of the same kidney. Relative blood flow puncture techniques. Free flow proximal intratubular pressure per gram tissue to juxtamedullary inner cortical (IC) and outer (Pf), "stop flow" (Ps), mean arterial, and colloid-osmotic pres- cortical (OC) glomeruli was determined by the ratio of micro- sure of the plasma protein (Pc0), were determined in guinea pigs spheres trapped in the respective region. IC/OC ratios fell from ranging in age from 1 to 56 days (27 animals). The values obtained 1.2 at birth to 0.25 at 14 days and remained relatively constant were used in the calculation of glomerular capillary pressure, thereafter. There was no correlation between IC/OC ratio and Pcap = Ps + Pco. and of the effective filtration pressure, Pcff = PAH extraction (EPAH). EPAH remained constant at 0.50 during Pcap — (Pf + Pco)- Free flow intratubular pressure increased from the first 40 days of life (adult EPAH = 0.85). IC/OC ratio de- 5.5 ± 0.3 during the 1st to 9.2 ± 0.2 (mean ± S. E.) during the clined as blood pressure rose from 30 to 70 mm Hg and remained 8th week of life, whereas capillary pressure increased from 21.2 ± relatively constant at blood pressures above 70 mm Hg. These 1.8 to 29.3 ± 1.0 mm Hg. Since the actual increase in capillary results suggest that there is a marked change in intrarenal blood pressure was about twice the increase in intratubular pressure, flow distribution during the first two weeks of life as more blood effective filtration pressure rose accordingly from 4.9 ± 0.4 to 9.4 is delivered to outer cortical nephrons with maturation. The ± 0.8 mm Hg. During the same period mean arterial pressure early large flow to juxtamedullary glomeruli suggests a large post- changed from 42.9 ± 2.2 to 58.5 ± 7.9 mm Hg. It appears, there- glomerular medullary flow. The lack of correlation between fore, that an increase in glomerular capillary pressure is an im- IC/OC ratio and EPAH suggests that the low EPAH in the new- portant factor in the increase in glomerular filtration rate that born period is not due solely to a large medullary flow. Finally, is observed with age. intrarenal flow distribution maturation is closely related to blood pressure maturation. Ontogeny of amino acid transport sites in kidney: specific and total activity. K. BAERLOCHER, C. CLOW, S. MACKENZIE and C. The effect of Na2SO4 on urinary acidification in the intact fetal SCRIVER. McGill Univ.-Montreal Children's Hosp. Res. Inst., lamb. EDDIE S. MOORE, CLARENCE W. DELANNOY, and JOHN B. Montreal, Que., Can. PATON (Intr. by Richard Behrman). Univ. of III. Coll. of Med. Urinary hyperexcretion of proline, hydroxyproline and glycine Chicago, III. is a defined component of the transient impairment in tubular ABSTRACTS 383 absorption of amino acids after birth in man and rat. In both liminary studies suggest that calculation of selectivity is possible species, loss of iminoaciduria precedes reduction of hyper- even at low levels of protein excretion by comparison of clearance glycinuria. This coincides with in vitro evidence in rat for phased of transferrin, IgG and tt2 macroglobulin performed on urine, in "activation" of substrate-specific membrane carriers, the one which the protein has been concentrated by lyophylization. for proline appearing early, that for glycine, late. "Activation" apparently involves appearance of new carrier proteins rather Plasma norepinephrine concentration before and after albumin than gain in energy coupling to existing carriers, since studies of infusion in nephrotic children. ROBERT C. KELSCH, GERALD S. amino acid interaction during influx, heteroexchange and inhibi- LIGHT, and WILLIAM J. OLIVER. Univ. of Mich. Med. Ctr., Ann tion of energy metabolism indicate a specific initial lack of rele- Arbor, Mich. vant carriers. However "maturation" of total amino acid trans- A reduction of effective plasma volume secondary to a decrease port in kidney also involves another component. By comparing in the quantity of circulating protein is postulated to initiate Vmax for uptake in vitro of proline, glycine and a-amino iso- edema formation in the nephrotic syndrome, however reduction butyric acid on carriers present from birth, we found their rela- of plasma volume has not been consistently demonstrated during tive capacities to increase synchronously after birth. This is com- active disease. Acute and chronic reduction of plasma volume is patible either with increasing membrane area or with more effi- associated with an increased excretion of norepinephrine, pre- cient coupling of energy to transport. Thus changes both in sumably secondary to increased sympathetic activity. We therefore specific activity of carriers and in total membrane activity charac- studied certain aspects of norepinephrine metabolism in thirteen terize ontogeny of amino acid transport in kidney. children with the active nephrotic syndrome. All children were on a lV^-2 mEq/kg/day sodium intake and no diuretic . Clinical-pathological correlations in the nephrotic syndrome. A Plasma norepinephrine concentration was measured on two con- report of the international study of in children. secutive mornings and again four hours later each day. Albumin CHESTER M. EDELMANN, JR., A. Einstein Coll. Med., N. Y. (6-18 grams) was infused 3 hours prior to the second blood 191 children with idiopathic nephrotic syndrome (absence of sample on the second day. All samples were obtained from the systemic disease or other known etiology) were studied from onset. antecubital vein after the subject had remained at 30 degrees tilt Age and sex distribution were as expected. Renal revealed l 4 for 20 minutes. Eight of the thirteen children had increased glomerulonephritis (GN) in A; of these A were steroid non- plasma norepinephrine concentrations in the early morning (> responsive (continued proteinuria after 8 weeks prednisone). Of 0.5 ng./ml). The plasma norepinephrine concentration measured patients with "minimal lesions" (ML), 5% were steroid non- l following albumin infusion was significantly reduced whereas that responsive; the other 95% were '/s frequent relapsers, /s in- obtained on the control day was not. Urinary excretion of frequent relapsers, and Ys nonrelapsers. In ML no difference in conjugated norepinephrine declined significantly within 48 hours response or course was found with sex or age of onset. The over- after the initiation of prednisone treatment in these subjects. all poorer prognosis in $ and in older children was due to under- These data suggest the presence of increased sympathetic activity lying GN. Only 38% with ML, but 52% with GN were $ . >!/2 during the active phase of the nephrotic syndrome which can be patients >8 years old had GN. Hematuria did not predict the altered by the infusion of albumin or the administration of clinical course in ML. Marked hematuria was present in 19% prednisone. with ML but 64% with GN. Thus the poor prognosis associated with hematuria is due to the likelihood of underlying GN. Despite striking exceptions, urinary selectivity index correlated in Familial nephrotic syndrome with nephrocalcinosis and tubular a general way with and steroid response. Immunization dysfunction. EDMUND C. BURKE, GUNNAR B. STICKLER, KEITH preceded onset only in patients with ML, suggesting that it may E. HOLLEY, and LADISLAV P. NOVAK, Mayo Clinic and Mayo be an etiologic factor. No correlations with histology or course Found., Rochester, Minn. were found with history of in patient or family, infection We have studied 5 children in 2 families, 3 boys in family A and preceding onset, urinary tract infection at onset, or family history 2 girls in family B, who had the onset of nephrotic syndrome in of renal disease. Although histology between groups based on early infancy. The syndrome proved to be steroid-resistant, al- father's occupation was similar, there were significantly more though there was no evidence of tubular failure initially. Growth nonrelapsing patients in the professional group. retardation, , and tetany appeared in several at an early age, and all manifested these symptoms eventually. Correlations of selectivity of protein excretion in childhood Glycosuria, aminoaciduria, and nephrocalcinosis also appeared. nephrotic syndrome. JOHN T. HERRIN, and A. SALTZMAN (Intro, Renal from 2 children in each family showed glomerular by John D. Crawford). Harvard Med. Sch., Mass. Gen. Hosp., proliferative changes, glomerular scarring, interstitial inflam- Children's Service, and Shriner's Burns Institute, Boston, Mass. mation, and microcalcinosis together with marked tubular Selectivity of proteinuria as measured by clearance ratios of atrophy. Autopsy studies were completed on 2 boys. Each boy transferrin and IgG were performed in 28 children with nephrotic died when about 8 years old. One girl is preterminal with renal syndrome. Selectivity correlated with response to steroid therapy, failure at 8 years of age. Hypertension was present only termi- histology when available (16 patients) and was not related to de- nally. The youngest boy in family A has not yet developed gree of proteinuria or altered by therapy. nephrocalcinosis. Total-body composition studies on 1 boy and 2 Radial diffusion methods (Mancini) using commercially pre- girls showed increased exchangeable sodium, increase in extracel- pared plates and values using the Ouchterlony method gave com- lular water, decrease in total body potassium, and decrease in in- parable results which remained constant, within the limits of the tracellular potassium. Whereas tubular failure previously has been method throughout repeated testing. reported in patients with long-standing nephrotic syndrome, we Critical evaluation of results shows that high protein excretion believe these cases differ in that they are familial and have in- is necessary for accurate prediction of steroid response. Pre- terstitial and nephrocalcinosis.